help please from the MN genetics experts

[Blandmum]

I know that Fact 8 linked hemophilia is X linked.

I have read in text books that it is fatal in females homozygous for the condition....however this is in an old text books and there is no supporting refernce.

So some questions.

Is this true?

If true why is the homozygous condition lethal in women while the since inheritance of the faulty gene and Y chromosome combo isn't lethal in males?

And I assume there are multiple mutations of the gene to explain the range of severity of the condition. Am I right?

I have googles and found nothing.

Help please???????

[Blandmum]

factor 8!

[bluebear]

Here's some up to date info - haven't got time to read it at the moment but it might answer your questions.

www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=books&doptcmdl=GenBookHL&term=Factor+VIII+AND+gene%5Bbook%5D+AND+411143%5Buid%5D&rid=gene.chapter.hemo-a#hemo-a.Carrier_Females

sorry can't do links with this keyboard!

[tamum]

\link{http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=306700\OMIM} is the best place to check stuff like this, it's updated regularly and is very comprehensive. I can't see any reason of earth why it shoudl be fatal in females, makes no sense. I don't know much about it but I am sure there are loads of different mutations- maybe some clustering at CpGs.

[bluebear]

OK, I had a quick scan of the site i gave the address for and can't see anything about fatality in homozygous females (akthough to be honest, didn't particularly mention homozygous females), but it would be very odd for X linked inheritance.
Lots of info about severity though.

(I found this site via the 'bookshelf' on pubmed - go to www.pubmed.com and put in your search term then select to search 'books' - it's great for human biology)

[alsochangedmyname]

Ha, my initial thought was about von Willebrand which isn't X-linked, never associated the X-linked haemophilia with females, but Tanum's link does mention some stuff about females affected by it (females homozygous).
One of the possibilies is that the female "comes" from 2 affected parents. Unusal but just wondering about various royal families who used to "intermarry"....

[Hallgerda]

I don't really know anything about this but...

could the condition be fatal in women when their periods start?

[Blandmum]

Facinating. ladies, ta very much for that.

I think I have tracked down the origin of the Homozygous female=lethal mutation....a very old publication in the 1920s

Looks like the old text book took it as gospel without data to support.

I couldn't think of a reason why it would be lethal either. made no logical sense

Ta muchly!

[Blandmum]

Yes it would, but they can treat the condition now with synthetic factor 8

[tamum]

That's a good point Hallgerda.

Alsochangedmyname, there are precedents for homozygous affected females for X linked diseases, it's not that uncommon, it was just the fatality bit that was surprising.

[Hallgerda]

Aha! I have just dug out my copy of \link{http://www.amazon.co.uk/exec/obidos/ASIN/0750911999/qid=1142414285/sr=1-1/ref=sr_1_0_1/202-3689863-0698257\this?tag=mumsnet&ascsubtag=mnforum-21 book}. On p59 it states "There have been only two or three girls in the whole of medical history, who were the offspring of cousin marriages, who were unlucky enough to inherit two X chromosomes from both sides of the same family, each with the gene for haemophilia. They manifested the same symptoms as male haemophiliacs suffer and invariably died at puberty, when they began to menstruate."

I wouldn't take this book as gospel; there's some bad stats in it, but as one of the authors is a Professor of Biology I would have more confidence in those aspects of the book.

[alsochangedmyname]

tanum, I suppose it's fairly logical, have heared about it for colour blindness (my dad colour blind, me carrier)it's just that I didn't think about it for haemohphilia as it remained just "text book knowledge".